The socioeconomic costs associated with health care affect all of society and effective treatments which reduce these costs are continuously sought and welcomed. One specific aspect of health care costs is the high cost associated with the care of premature infants. Premature infants are born of mothers whose pregnancy has not reached full term. Typically premature infants suffer from a variety of health problems due, at least in part, to their low birth weight. Premature infants require extensive medical care, the cost of which represents a significant burden on the health care system.
The premature birth of an infant results directly from the mother's premature labor. The onset of premature labor is characterized by uterine contractility. The contraction of the uterus is a response to a complex biological process in which a class of compounds known as prostaglandins play a controlling role. Prostaglandin synthesis occurs in tissues throughout the body, including the tissues of the uterus and cervix. In a pregnant woman, prostaglandin production increases during the term of pregnancy and culminates with a sharp increase at parturition. Because prostaglandins induce smooth muscle contraction, high uterine concentrations of these compounds at parturition initiate contractility and the onset of labor. This increase in uterine contractility is associated with a process known as "cervical ripening," which in turn progresses to cervical dilation. It is generally believed that the underlying mechanism associated with such changes in the cervix is similar to the inflammatory response which governs other biological processes. Among the changes that occur in the cervix are edema, increased vascular permeability with enzymatic changes and the resultant breakdown of collagen. Many of these changes are mediated by prostaglandins and leukotrienes, and cervical tissue levels of these inflammatory mediators are sharply increased at term.
The intermediacy and effectiveness of prostaglandins in the onset of labor is further evidenced by the long established use of prostaglandin E2 as a potent labor inducer. Conversely, effective inhibition of prostaglandin synthesis would lead to the suppression of uterine contractility and the delay of the onset of labor. Where labor is premature, the inhibition or prevention of prostaglandin synthesis may serve to avert the labor, and thereby avoid premature birth.
Prostaglandins are produced biosynthetically throughout the body. Prostaglandins are derived from enzymatic action on a common substrate, arachidonic acid. The first step in prostaglandin synthesis is the oxygenation of arachidonic acid by the enzyme cyclo-oxygenase. The oxygenated prostaglandin precursors are subject to further enzymatic processes which provide the various members of the prostaglandin family, including prostaglandin E2. Closely related in structure and function to the prostaglandins are a family of compounds known as leukotrienes. Leukotrienes are also derived from arachidonic acid metabolism, but through the lipoxygenase pathway. Like prostaglandins, leukotrienes enhance smooth muscle contraction and have also been implicated in uterine contractility.
Arachidonic acid is an essential fatty acid consisting of twenty carbon atoms and containing four carbon-carbon double bonds. By virtue of the position of carbon-carbon double bond at the methyl (omega) end of the hydrocarbon chain, it is classified as an omega-6 fatty acid. A closely related family of fatty acids are the omega-3 fatty acids. In addition to double bond position, omega-6 and omega-3 fatty acids may also be distinguished by their origins. The precursors to these fatty acids are derived from plants which are in turn further metabolized in animals to provide the long chain polyunsaturated acids. Omega-6 fatty acids may be found predominantly in land animals, while omega-3 fatty acids are abundant in fish.
The beneficial health effects of fish rich diets, such as overall cardiovascular health, have been attributed to omega-3 fatty acids. Corey et al., Proc. Nat. Acad. Sci. 80:3581-84 (1983). In addition, diets rich in omega-3 fatty acids have been associated with prolonged gestation and larger birth weights. Olsen et al., Lancet ii:367-69 (1986). In contrast, diets low in omega-3 fatty acids delivered earlier and smaller babies. Crawford et al., Prog Lipid Res. 25:249-54 (1986). The oral administration of omega-3 fatty acids has been shown to prolong gestation by delaying the onset of labor. Leaver et al., Prog. Lipid Res. 25: 143-46 (1986).
Oral administration of omega fatty acids, however, has limited effectiveness and suffers from several drawbacks. Fatty acids that are taken orally are subject to gastrointestinal absorption and metabolism. In order to achieve delivery of effective quantities of fatty acids to the uterus, large quantities must be administered. To compensate for the reduction of active compound reaching the targeted organ, increased dosages of fatty acids are required. In addition, oral administration of fatty acids is not tissue specific and the dosage is distributed throughout the body. Because these omega fatty acids affect biological processes beyond prostaglandin synthesis, side effects associated with oral administration have been observed. For example, omega fatty acids are known to interfere with normal platelet function, and oral administration generally results in the increased danger of bleeding. Rogers et al., Atherosclerosis 63:137-43 (1987). The effect of omega fatty acids on platelet function also adversely affects capillary fragility. The increased dosages necessary for effective reduction of uterine contraction serves to exacerbate the side effects due to interference with platelet function.
In general, agents which inhibit uterine contractility are known as "tocolytic" agents. Turbutaline sulphate is perhaps the most common tocolytic agent presently employed in obstetric practice (although not approved by the FDA for this indication), and is administered either orally or as a subcutaneous injection. However, serious adverse reactions may occur following administration of turbutaline sulphate to women in labor. In the mother, the potential adverse reactions include increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmia, pulmonary edema and myocardial ischemia. In addition, fetal heart rate and neonatal hypoglycemia may occur as a result of maternal administration (see Zurich et al., Physicians Desk Reference, 1993 Edition, Medical Economics Data, p. 1061).
Magnesium sulfate (i.e., epsom salts) has also been used to inhibit uterine contractility. Administration of this tocolytic agent is by continuous intravenous infusion. As with turbutaline sulphate, magnesium sulfate can produce undesirable side effects, including maternal cardiac and ECG changes, depression of neuromuscular function and somnolence. Moreover, this agent must be used with caution in patients with impaired renal function and, since magnesium sulfate crosses the placenta, it may result in adverse effects in the fetus.
While other tocolytic agents, such as indomethacin, have been used with limited success, reports of adverse fetal and neonatal effects (including oligohydramnios, premature closure of the ductus arteriosis and pulmonary hypertension) have limited their application. For example, in one series of experiments, postpartum hemorrhage was observed in 19% of mothers who received a single does of indomethacin (Keiss et al., Intl. J Gynaecol. Obstet. 44:787, 1974).
Accordingly, there is a need in the art for improved compositions and methods to inhibit uterine contractility and prevent premature labor. The present invention fulfills these objectives, and provides further related advantages.